Macquarie University
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Identification and characterization of a novel isoform of fused in sarcoma and its role in amyotrophic lateral sclerosis

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posted on 2022-03-28, 12:30 authored by Marta Vidal Robau
The fused in sarcoma (FUS) gene is mutated in 4% of familial cases of Amyotrophic lateral sclerosis (ALS) and 1% of sporadic cases. Moreover, FUS immunoreactive inclusions are present in both ALS patients. Importantly, mutations in FUS account for a particularly aggressive, juvenile form of the disease. Hence, elucidating the pathological role of FUS in ALS is crucial for understanding the disease. While the mechanisms underlying neurodegeneration in ALS are not fully understood, defects in alternative splicing have been previously associated with ALS disease pathology. Additionally, alternative spliced forms of proteins linked to ALS, have also beenimplicated. This thesis focuses on the study of a newly identified, extracellular isoform of FUS, which was termed 'FUSEC'. FUSEC has a unique N-terminus sequence but shares its C-terminus with canonical FUS. For FUS, the most abundant ALS mutations are enriched at the C-terminus. Here it was confirmed FUSEC expression at the mRNA and protein level. Furthermore, it was demonstrated it is N-glycosylated mostly with complex N-glycans, and this regulates its secretion. Also it was studied its intracellular localization and its potential normal functions. Finally, the role of FUSEC in ALS was examined. FUSEC bearing ALS mutations demonstrated inclusion formation, induction of ER stress and Golgi fragmentation and finally apoptosis, key cellular features of ALS. The discovery of a new alternatively spliced isoform of FUS provides novel insights into the pathogenic mechanisms implicated in ALS.


Table of Contents

1. General introduction -- 2. Material and methods -- 3. Identification of a novel extracellular isoform of FUS -- 4. Characterization of FUSEC -- 5. Examining the role of FUSEC in ALS -- 6. General discussion -- 7. References -- 8. Appendix.


Empirical thesis. Bibliography: pages 210-256

Awarding Institution

Macquarie University

Degree Type

Thesis PhD


PhD, Macquarie University, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Media, Music, Communication and Cultural Studies

Year of Award


Principal Supervisor

Julie Akin

Additional Supervisor 1

Audrey Ragagnin

Additional Supervisor 2

Albert Lee


Copyright Marta Vidal Robau 2018. Copyright disclaimer:




1 online resource (xxvi, 320 pages) colour illustrations

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